Abstract
There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological, and behavioral techniques, we show that pathological AICD levels weaken CA1 neuron firing activity through a gene-transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the γ-frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal aging to AD.
Highlights
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder, with increasing prevalence in aging populations
AICD Weakens CA1 Pyramidal Neuron Firing in the g Frequency Range through a Gene-TranscriptionDependent Mechanism First, we examined the impact of AICD on neuron firing activity
As illustrated (Figure 1D), when a current injection of 300 pA was applied, AICD or AICDnls neurons fired at a lower frequency than GFP or AICD from the nucleus (AICDnes) neurons, a difference that was systematically observed for current injections higher than 300 pA
Summary
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder, with increasing prevalence in aging populations. Comprehensive characterization of mutant APP-overexpressing transgenic mice have reported changes of firing homeostasis in both excitatory and inhibitory neurons of the hippocampus (Brown et al, 2011; Hazra et al, 2013; Kaczorowski et al, 2011; Kerrigan et al, 2014; Minkeviciene et al, 2009; Wykes et al, 2012), the entorhinal cortex (Marcantoni et al, 2014), the cortex (Hazra et al, 2013; Verret et al, 2012), and the cerebellum (Hoxha et al, 2012), but the entities behind these firing modifications are yet to be identified In these models, the contribution of individual peptides generated from abnormal or enhanced proteolytic APP cleavage cannot be dissociated. Approaches allowing to decipher the contribution of individual APP fragments to the modulation of neuron firing, are needed and will be crucial to fully understand the complexity of AD pathogenesis
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